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Staff photo Mikael Elofsson

Mikael Elofsson

Dean Faculty of Science and Technology

Works at

Affiliation
Location
KB.C4, Linnaeus väg 10, (rum: B4.25.07) Umeå universitet, 901 87 Umeå

The group is currently engaged in three reserach areas:

  • Inhibitors of bacterial virulence systems
  • Chemical probes to study ADP-ribosyltransferases
  • Antiviral small molecules and glycoconjugate

 

Inhibitors of bacterial virulence systems
Using a chemistry based multidisciplinary approach we explore various aspects of bacterial virulence. The ultimate goal is to generate knowledge that will lead to highly specific antibacterial regimens that counteract the virulence mechanisms of the pathogens and minimize the risks for development of resistance. Virulence can broadly be defined as the capacity of a microorganism to cause disease. The main focus is on the evolutionary conserved type III secretion (T3S) virulence systems that are shared by several clinically important mammalian pathogens including Yersinia spp., Salmonella spp., Shigella spp., Pseudomonas aeruginosa, enteropathogenic and enterohaemorrhagic Escherichia coli, and Chlamydia spp. During the infection the bacterium adheres to a eukaryotic cell membrane and with the T3S machinery it injects a set of toxins into the lumen of the target cell and thereby subvert host defense mechanisms. We use screening-based strategies to identify natural and synthetic T3S inhibitors and use total synthesis, statistical molecular design, structure-based design and computation of quantitative structure-activity relationships in the subsequent optimization. Compounds are evaluated in a wide variety of assays including cell-based and in vivo infection models with focus on Yersinia spp., Pseudomonas aeruginiosa, and Chlamydia spp. Currently we have identified and optimized virulence inhibitors active against a number of bacterial species and established efficacy in vitro and in vivo.

Chemical probes to study human ADP-ribosyltransferases
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. ADP-ribosylation plays a critical role in cell differentiation, proliferation, genome integrity and cell-survival but the exact molecular mechanisms and its role in epigenetics remain elusive. The human diphtheria toxin-like ADP-ribose transferase (ARTD) family, also known as the poly (ADP-ribose) polymerase (PARP) family is composed of 17 members that all share a catalytic ADP ribose transerase domain. The most common human enzyme ARTD1/PARP1, and its closest relative ARTD2/PARP2, are the most studied proteins in the family and ARTD1 has been a target for drug discovery for more than a decade. Very little is however known on the biological function of the remaining family members. Our project aims to develop small molecules, chemical probes, to study ADP-ribosylation and its potential roles in epigenetic signaling. We have adopted a structure-based approach to develop potent chemical probes that show specificity towards individual members of the ARTD family. As a basis for this program we assembled a collection of compounds based on known ART inhibitors, and characterized their interactions with the catalytic domains across the entire family. In addition, we solved crystal structures of ART catalytic domains in complex with compounds identified as hits from this collection. Collectively these data provide insights into the structural determinants of inhibitor specificity, and has been used as starting points in a structure-guided medicinal chemistry program to generate selective and potent inhibitors of human ARTDs as well bacterial ADP-ribosylating toxins such as ExoS from P. aeruginosa.

Antiviral small molecules and glycoconjugates
Human adenoviruses are very common pathogens with more than 50 different serotypes forming six different species, A to F. Adenoviruses are associated with a wide variety of clinical symptoms in humans, such as upper respiratory illness, acute respiratory disease, gastroenteritis, hemorrhagic cystitis, and also keratoconjunctivitis. Although these infections can develop into severe diseases they are commonly self-limited in otherwise healthy individuals. The problem is however much more pronounced in immunocompromised individuals. Today there is no formally approved therapy for adenovirus infection and existing antiviral drugs give inconsistent results. To address this shortcoming we have employed strategies based on glycoconjugates and small drug-like molecules to target different steps of the adenoviral life cycle. Such molecules constitute research tools for manipulation of the viral life cycle and starting points for development of antiadenoviral therapies. This knowledge is also transferred into design and synthesis of compounds against other viruses e.g. Rift Valley fever virus and Zika virus.

2020
Viruses, MDPI 2020, Vol. 12, (3)
Gwon, Yong-Dae; Strand, Mårten; Lindquist, Richard; et al.
2020
Scientific Reports, Nature Publishing Group 2020, Vol. 10, (1)
Sundin, Charlotta; Zetterström, Caroline E.; Vo, Duy Duc; et al.
2019
Cell Death and Differentiation, Nature Publishing Group 2019, Vol. 26, (9) : 1615-1630
Beck, Carole; Rodriguez-Vargas, José Manuel; Boehler, Christian; et al.
2019
Viruses, MDPI 2019, Vol. 11, (5)
Chandra, Naresh; Frängsmyr, Lars; Imhof, Sophie; et al.
2019
Frontiers in Cellular and Infection Microbiology, Frontiers Media S.A. 2019, Vol. 9
Massai, Francesco; Saleeb, Michael; Doruk, Tugrul; et al.
2019
Molecular plant pathology, John Wiley & Sons 2019, Vol. 20, (1) : 20-32
Puigvert, Marina; Sole, Montserrat; Lopez-Garcia, Belen; et al.
2019
Biochemical and Biophysical Research Communications - BBRC, Elsevier 2019, Vol. 511, (1) : 117-121
Tükenmez, Hasan; Edström, Isabel; Kalsum, Sadaf; et al.
2018
SLAS DISCOVERY, Sage Publications 2018, Vol. 23, (4) : 353-362
Ekblad, Torun; Verheugd, Patricia; Lindgren, Anders E.; et al.
2018
Scientific Reports, NATURE PUBLISHING GROUP 2018, Vol. 8
Islam, Md. Koushikul; Strand, Mårten; Saleeb, Michael; et al.
2018
Nature Communications, Nature Publishing Group 2018, Vol. 9
Karlberg, Tobias; Hornyak, Peter; Pinto, Ana Filipa; et al.
2018
Organic Letters, American Chemical Society (ACS) 2018, Vol. 20, (21) : 6650-6654
Krzyzanowski, Adrian; Saleeb, Michael; Elofsson, Mikael
2018
ChemistryOpen, Wiley-VCH Verlagsgesellschaft 2018, Vol. 7, (12) : 953-956
Kumar, Arvind; Saleeb, Michael; Werz, Dominik; et al.
2018
Frontiers in Microbiology, Frontiers Media S.A. 2018, Vol. 9
Mojica, Sergio; Eriksson, Anna U.; Davis, Rohan A.; et al.
2018
European Journal of Medicinal Chemistry, Elsevier 2018, Vol. 143 : 1077-1089
Saleeb, Michael; Mojica, Sergio; Eriksson, Anna U.; et al.
2018
European Journal of Medicinal Chemistry, Elsevier 2018, Vol. 143 : 568-576
Saleeb, Michael; Sundin, Charlotta; Aglar, Öznur; et al.
2018
SLAS Discovery, Sage Publications 2018, Vol. 23, (8) : 815-822
Zetterström, Caroline E.; Uusitalo, Pia; Qian, Weixing; et al.
2017
Antimicrobial Agents and Chemotherapy, American society for microbiology 2017, Vol. 61, (10)
Mojica, Sergio A.; Salin, Olli; Bastidas, Robert J.; et al.
2017
ACS Combinatorial Science, American Chemical Society (ACS) 2017, Vol. 19, (6) : 370-376
Qin, Liena; Vo, Duc-Duy; Nakhai, Azadeh; et al.
2017
Journal of enzyme inhibition and medicinal chemistry (Print), Vol. 32, (1) : 513-521
Sunduru, Naresh; Svensson, Mona; Cipriano, Mariateresa; et al.
2017
Journal of antibiotics (Tokyo. 1968), Japan Antibiotics Research Association 2017, Vol. 70, (9) : 937-943
Uusitalo, Pia; Hägglund, Ulrik; Rhöös, Elin; et al.
2016
Frontiers in Microbiology, Vol. 7
Huerta-Uribe, Alejandro; Marjenberg, Zoe R.; Yamaguchi, Nao; et al.
2016
European Journal of Organic Chemistry, (3) : 426-429
Lindgren, Anders E. G.; Oberg, Christopher T.; Hillgren, J. Mikael; et al.
2016
Journal of Biomolecular Screening, Vol. 21, (6) : 590-595
Pinto, Ana Filipa; Ebrahimi, Mahsa; Saleeb, Michael; et al.
2016
Advanced Synthesis and Catalysis, Wiley-VCH Verlagsgesellschaft 2016, Vol. 358, (24) : 4085-4092
Vo, Duc Duy; Elofsson, Mikael
2015
European Journal of Medicinal Chemistry, Elsevier 2015, Vol. 103 : 191-209
Caraballo, Remi; Larsson, Mikael; Nilsson, Stefan K.; et al.
2015
Organic and biomolecular chemistry, Vol. 13, (35) : 9194-9205
Caraballo, Rémi; Saleeb, Michael; Bauer, Johannes; et al.
2015
European Journal of Medicinal Chemistry, Vol. 95 : 546-551
Ekblad, Torun; Lindgren, Anders E. G.; Andersson, C. David; et al.
2015
Journal of antibiotics (Tokyo. 1968), Vol. 68, (10) : 609-614
Hakala, Elina F.; Hanski, Leena; Uvell, Hanna; et al.
2015
Journal of Biomolecular Screening, Vol. 20, (2) : 285-91
Stylianou, Marios; Uvell, Hanna; Lopes, Jose Pedro; et al.
2015
European Journal of Medicinal Chemistry, Vol. 101 : 595-603
Sunduru, Naresh; Salin, Olli; Gylfe, Åsa; et al.
2014
Journal of Bacteriology, American Society for Microbiology 2014, Vol. 196, (16) : 2989-3001
Bao, Xiaofeng; Gylfe, Åsa; Sturdevant, Gail L.; et al.
2014
Journal of natural products (Print), Washington: American Chemical Society (ACS) 2014, Vol. 77, (12) : 2633-2640
Davis, Rohan A.; Beattie, Karren D.; Xu, Min; et al.
2014
ChemMedChem, Vol. 9, (10) : 2309-2326
Horvath, Dragos; Lisurek, Michael; Rupp, Bernd; et al.
2014
Biochemical and Biophysical Research Communications - BBRC, Elsevier 2014, Vol. 450, (2) : 1063-1069
Larsson, Mikael; Caraballo, Rémi; Ericsson, Madelene; et al.
2014
Methods in Molecular Biology, Springer 2014, Vol. 1056 : 169-188
Lindgren, Anders E G; Larsson, Andreas; Linusson, Anna; et al.
2014
Antimicrobial Agents and Chemotherapy, American Society for Microbiology 2014, Vol. 58, (5) : 2968-2971
Marwaha, Sania; Uvell, Hanna; Salin, Olli; et al.
2014
Journal of Inorganic Biochemistry, Elsevier 2014, Vol. 138 : 1-8
Rzhepishevska, Olena; Hakobyan, Shoghik; Ekstrand-Hammarström, Barbro; et al.
2014
Marine Drugs, MDPI 2014, Vol. 12, (2) : 799-821
Strand, Mårten; Carlsson, Marcus; Uvell, Hanna; et al.
2014
Antimicrobial Agents and Chemotherapy, Vol. 58, (7) : 4123-4130
Sun, Kun; Bröms, Jeanette; Lavander, Moa; et al.
2014
Molecular plant pathology, Wiley-Blackwell 2014, Vol. 15, (1) : 44-57
Yang, Fan; Korban, Schuyler S.; Pusey, P. Lawrence; et al.
2013
Journal of Bacteriology, Washington DC, USA: American Society for Microbiology 2013, Vol. 195, (18) : 4221-4230
Engström, Patrik; Nguyen, Bidong D.; Normark, Johan; et al.
2013
Journal of Medicinal Chemistry, American Chemical Society (ACS) 2013, Vol. 56, (23) : 9556-9568
Lindgren, Anders E. G.; Karlberg, Tobias; Ekblad, Torun; et al.
2013
ACS Chemical Biology, Vol. 8, (8) : 1698-1703
Lindgren, Anders E. G.; Karlberg, Tobias; Thorsell, Ann-Gerd; et al.
2013
PLoS ONE, Public Library Science 2013, Vol. 8, (12)
Zetterström, Caroline E.; Hasselgren, Jenny; Salin, Olli; et al.
2012
Journal of Medicinal Chemistry, Vol. 55, (17) : 7706-7718
Andersson, C David; Karlberg, Tobias; Ekblad, Torun; et al.
2012
Bioorganic & Medicinal Chemistry Letters, Elsevier 2012, Vol. 22, (10) : 3550-3553
Enquist, Per-Anders; Gylfe, Åsa; Hägglund, Ulrik; et al.
2012
Advances in Yersinia Research, New York: Springer 2012 : 357-363
Eriksson, Jonas; Grundström, Christin; Sauer-Eriksson, A Elisabeth; et al.
2012
International Journal of Antimicrobial Agents, Vol. 40, (4) : 354-360
Forthal, Donald N; Phan, Tran B; Slepenkin, Anatoly V; et al.

Research projects

1 January 2017 until 31 December 2017